The proposed research involves defining the detailed mechanisms by which thyroid hormones regulate biologic processes in mammalian cells. A cell culture system has been developed which is responsive to physiologic concentrations of the thyroid hormones. In this system thyroid hormones induce a three-fold increase in the rate of cell growth, glucose utilization and growth hormone secretion. In addition at identical physiological hormone concentrations prolactin secretion is inhibited in GH1 cell cultures. Studies on the early effects of thyroid hormones on cultured GH1 cells suggest an early effect at the level of DNA transcription. Nuclear receptor sites which appear to mediate the action of the thyroid hormones have been characterized in intact cells, isolated nuclei, and in solubilized nuclear extracts. The nuclear binding activity has characteristics of a non-histone protein and is relatively stable after extracted from nuclei in a soluble form. The initial events in the action of the thyroid hormones will be characterized with respect to early observed changes on nuclear template activity and RNA polymerase. The effect of thyroid hormone with respect to synthesis on transfer RNA, ribosomal RNA and total poly-A rich messenger RNA and hetergenous nuclear RNA will be defined. In addition we hope to purify the nuclear receptor for thyroid hormones and by reconstitution studies with chromatin constituents in vitro attempt to define the role of the receptor in initiating the cellular action of thyroid hormone.